<p>Pepper (<i>Piper nigrum</i> Linn) is widely used as a seasoning in the culinary industry, and alkamides are its major active components. Among them, piperine (PIP) is a key natural alkamide known for its diverse pharmacological properties, including anti-inflammatory, antioxidant, anticonvulsant, neuroprotective, anticancer, antibacterial, and antiparasitic effects. In addition, PIP is widely utilized as a bioenhancer. Notably, it has garnered increasing attention for its potential as a natural phytochemical in the treatment of various inflammatory disorders. This review aims to summarize the extraction of alkamides as well as their role in inflammatory diseases by detailing its mechanisms of action and identifying potential anti-inflammatory targets. Following PRISMA guidelines, we comprehensively summarized the regulatory effect of PIP on inflammation-related diseases involve the nervous system, cardiovascular system, gastrointestinal tract and other areas and explained the pharmacological properties and mechanism. These review consolidate the latest research on alkamides and provide a foundation for the potential development of PIP as a natural anti-inflammatory agent in both the food and pharmaceutical industries.</p>